Urease Inhibition Mechanisms in Infectious Diseases

Urease, a nickel-dependent metalloenzyme produced by diverse pathogens, catalyses the hydrolysis of urea into ammonia and carbon dioxide, a reaction central to microbial survival in hostile environments and virulence in diseases such as peptic ulcers, urinary tract infections and respiratory conditions. Elevated urease activity contributes to local pH modulation, tissue damage and immune evasion, making the enzyme a prime target for therapeutic intervention. Inhibitors may engage the active site by coordinating to nickel ions, occupying substrate binding pockets or covalently modifying key residues. Strategies encompass metal chelators, transition-state analogues, thiol-targeting agents and allosteric modulators, each offering distinct affinities and selectivities. Recent structural insights reveal how small molecules can exploit the bridged Ni–Ni centre or mobile flap elements to induce conformational changes that impair catalysis. Effective urease inhibitors hold promise for adjunct treatments against Helicobacter pylori, Proteus mirabilis and Klebsiella species, with implications for reducing antibiotic resistance and toxicity. Ongoing research aims to optimise potency, pharmacokinetics and safety profiles to translate mechanistic discoveries into clinically useful agents.

Research from Nature Portfolio

A comprehensive screening of over seventy compounds under uniform conditions has elucidated diverse inhibition patterns against bacterial ureases and purified enzyme preparations. Several metal-binding agents, including novel chelators and organosulphur derivatives, were found to disrupt nickel uptake and coordination, thereby diminishing enzymatic activity in Klebsiella pneumoniae cultures. In parallel, certain polycarboxylates exhibited unexpected stimulatory effects on metal import while still attenuating ureolysis, highlighting the nuanced relationship between cellular metal homeostasis and enzyme function. This work underscores the potential of targeting accessory pathways of urease maturation alongside direct active-site engagement for broad-spectrum inhibition strategies.

Urease Inhibition Mechanisms in Infectious Diseases publication trend

The graph below shows the total number of articles in urease inhibition mechanisms in infectious diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Urease: A nickel-dependent enzyme that catalyses the conversion of urea into ammonia and carbon dioxide.

Ureolysis: The enzymatic reaction in which urea is hydrolysed by urease to generate ammonia and carbon dioxide.

Metalloenzyme: An enzyme that requires a metal ion, such as nickel, for catalytic activity.

Chelator: A compound capable of binding and sequestering metal ions, often used to disrupt metalloenzyme function.

Competitive inhibition: A mechanism in which an inhibitor competes with the substrate for binding to the active site of an enzyme.

Covalent inhibitor: A molecule that forms a stable covalent bond with an enzyme’s active-site residue, leading to irreversible or slowly reversible inhibition.

References

1. Optimized Ebselen-Based Inhibitors of Bacterial Ureases with Nontypical Mode of Action. Journal of Medicinal Chemistry (2023).
2. Inhibitory activity of catecholic phosphonic and phosphinic acids against Helicobacter pylori ureolysis. European Journal of Medicinal Chemistry (2023).
3. The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate. JBIC Journal of Biological Inorganic Chemistry (2020).
4. The Emerging Role of Urease as a General Microbial Virulence Factor. PLOS Pathogens (2014).
5. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Scientific Reports (2020).